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. 2020 Feb 10;12(2):411. doi: 10.3390/cancers12020411

Figure 1.

Figure 1

Therapeutic strategies for targeting the epidermal growth factor receptor (EGFR)/A disintegrin and metalloproteinase (ADAM17) axis. (a) pro-EGFR ligands are membrane-bound and require proteolytic cleavage by ADAM17 to generate ‘mature’ solubilized ligands that can bind to the EGF receptor. Ligand-bound EGFR can then (homo) dimerize, auto-phosphorylate, and initiate downstream signaling. (b) anti-EGFR designed ankyrin repeat protein (DARPin) E01 binds to EGFR in an antagonistic manner, preventing ligand binding and subsequent receptor activation. (c) ligand shedding can be prevented by inhibiting ADAM17 activity; for instance, by using recombinant inhibitory prodomain of ADAM17 (TPD) to block the catalytic site of active ADAM17 and preventing release of EGFR ligands. (d) the bispecific inhibitor (E01-GS-TPD) combines the activities of DARPin E01 and recombinant TPD by fusing the two modules together through a flexible glycine serine linker.